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Extranuclear estrogen receptor-[alpha] stimulates NeuroD1 binding to the insulin promoter and favors insulin synthesis
- Source :
- Proceedings of the National Academy of Sciences of the United States. July 20, 2010, Vol. 107 Issue 29, p13057, 6 p.
- Publication Year :
- 2010
-
Abstract
- Estrogen receptors (ERs) protect pancreatic islet survival in mice through rapid extranuclear actions. ER[alpha] also enhances insulin synthesis in cultured islets. Whether ERa stimulates insulin synthesis in vivo and, if so, through which mechanism(s) remain largely unknown. To address these issues, we generated a pancreas-specific ERa knockout mouse (PER[alpha][KO.sup.-/-]) using the Cre-loxP strategy and used a combination of genetic and pharmacologic tools in cultured islets and [beta] cells. Whereas 17[beta]-estradiol (E2) treatment up-regulates pancreatic insulin gene and protein content in control ERcdox/lox mice, these E2 effects are abolished in PER[alpha][KO.sup.-/-] mice. We find that E2-activated ER[alpha] increases insulin synthesis by enhancing glucose stimulation of the insulin promoter activity. Using a knock-in mouse with a mutated ER[alpha] eliminating binding to the estrogen response elements (EREs), we show that E2 stimulation of insulin synthesis is independent of the ERE. We find that the extranuclear ER[alpha] interacts with the tyrosine kinase Src, which activates extracellular signal-regulated [kinases.sub.1/2], to increase nuclear localization and binding to the insulin promoter of the transcription factor NeuroD1. This study supports the importance of ERa in [beta] cells as a regulator of insulin synthesis in vivo. diabetes | islet doi/ 10.1073/pnas.0914501107
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 107
- Issue :
- 29
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.233406577